Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2000-02-17
2002-11-19
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
Reexamination Certificate
active
06482809
ABSTRACT:
The invention relates to the use of tiludronic acid, one of its pharmaceutically acceptable salts or one of its hydrates in the preparation of a medicinal product for preventing and treating osteoporosis in poultry, and more particularly in hens.
Female birds have a bone metabolism which is particularly stressed with the aim of producing eggshells, which are rich in minerals, the main one of which is calcium. Bones in female birds fulfil two essential functions: a mechanical function, common to all vertebrates, giving the properties of maintaining the body in space, and a physiological function which is specific to female birds, by forming a calcium reserve which can readily be mobilized for the purpose of producing eggshells. The mechanical function is provided by two types of bone: the cortical bone constituting the outer sheath of the bones, and the trabecular bone constituting bony frames oriented along the lines of force inside the bones. The physiological function is essentially provided by a third type of bone, the medullary bone which occupies the cavities of certain long bones or flat bones. Medullary bone develops between the frames of the trabecular bone. This bone is very fragile and thus provides no mechanical function.
During laying periods, medullary bone undergoes cycles of resorption-formation, each cycle being accompanied by the formation of an egg. On being resorbed, the medullary bone releases a large amount of calcium required for the production of the eggshell. The formation which accompanies this resorption allows the reconstitution of the medullary calcium reserve, which will be mobilized in the next cycle.
Among female birds, the hen, in particular hens which lay eggs intended for human consumption, is the species whose bone metabolism is greatly stressed. h
Specifically, the constant progress in the fields of genetic selection and nutrition have led over the last 30 years to a uniform increase in the number of eggs laid per hen. It is now common for a hen to lay more than 300 eggs in a laying year. At the height of the productive phase, the hen lays one egg a day. Paradoxically, this change has been accompanied by a reduction in the size of the animals and thus, in particular, in the volume of the calcium reserve represented by the skeleton.
Bone metabolism in hens has still not been studied exhaustively. However, the changes which medullary bone and structural bone undergo in relation to laying are beginning to be better understood (see for example the articles by Wilson S. et al., 1992
, Res. Vet. Sci
., 53, 52-58, by Miller S. C., pp. 103-116 and by Whitehead C. C. et al., pp. 265-280 published in 15 the book “Bone Biology and Skeletal Disorders in Poultry”, 1992, edited by C. C. Whitehead, Carfax Publishing Company). As laying proceeds, the volume of medullary bone gradually increases so as to ensure production of the eggshell and maintenance of this production over time. The calcium stored in the medullary bone originates mainly from dietary calcium. However, the structural bone also participates in constituting the medullary calcium reserve. Thus, gradually as laying proceeds, while the medullary bone undergoes permanent remodelling at each laying cycle, the structural bone (cortical bone and trabecular bone) undergoes a resorption, releasing calcium which is then stored in the medullary bone. This resorption is not compensated for by the formation of new structural bone. The result of this phenomenon is a loss of structural bone during laying without the bone mineralization being affected. This characterizes osteoporosis in hens. This gradual process of bone loss is preceded by another loss of structural bone, this time accompanying the formation of medullary bone, this formation beginning with the development of ovarian follicles about 2 weeks before commencing laying (Wilson S. et al.,
Res. Vet. Sci
., 1998, 64, 37-40).
Thus, osteoporosis begins early in laying hens, from the moment they reach sexual maturity: the loss of structural bone at this stage accompanies the formation of medullary bone. It continues throughout laying: it then accompanies the remodelling of medullary bone which is essential for the production of eggshells.
The consequences of osteoporosis in hens are of diverse nature: medical, well-being and economic. Specifically, the loss of cortical and trabecular bone substance is a cause of an embrittlement of the skeleton leading to the occurrence of spontaneous fractures during laying or of fractures caused by handling of the animals at the end of laying, during the journey to the abattoir. Locomotor disorders are associated with embrittlement of the skeleton, to the point of reducing or even preventing movement by the animal, which ends up by no longer being able to feed, and dies. The well-being of the animal is thus placed in doubt (pain of the fractures, limited movement, poor feeding). Finally, from the economic standpoint, osteoporosis generates losses associated with the mortality, the reduction in egg production and the lack of economic value of the carcasses of hens bearing fractures.
Due to the consequences it entails, osteoporosis is one of the major preoccupations of the industry of rearing hens which lay eggs intended for human consumption (Knowles T. G. et al., 1998
, Poultry Science
, 77, 1798-1802). The search for solutions for reducing the magnitude of the osteoporosis process in laying hens corresponds to a great need of this industry.
Bisphosphonic acid derivatives, or bisphosphonates, of medical interest are now well known. Their pharmacological properties and their therapeutic uses in mammals, especially in man, are well documented. Bisphosphonic acid derivatives exert anti-resorptive properties on bone and a regulatory action on bone remodelling. The main cell target of these compounds is the osteoclast, which is the cell responsible for bone resorption. The mechanism of cellular action is in the process of being elucidated. It now appears that within the family of bisphosphonates, it is possible to distinguish two groups of compounds which act differently on the metabolism of the osteoclast: the compounds lacking a nitrogen function, in particular an amine function, and the compounds possessing such a function. The first group comprises compounds such as etidronic acid, clodronic acid or tiludronic acid. These compounds partly exert their cytotoxic action on the osteoclasts via metabolytes formed in the cell; these metabolytes are non-hydrolysable nucleotide analogues of ATP (Auriola S. et al., 1997
, J. Chromat. B
, 704, 187-195, Rogers M. J. et al., 1999, Bone, 24, 73S-79S). The second group (bisphosphonates containing a nitrogen function) comprises compounds such as pamidronic acid, alendronic acid, risedronic acid and ibandronic acid. These compounds exert a cytotoxic action via inhibition of the mevalonate metabolic pathway, leading to the absence of activation of proteins required for the osteolytic action of the osteoclasts (Luckman S. P., 1998
, J. Bone Miner. Res
., 13, 581-589).
This mode of action which is different at the cellular level corresponds to a difference in the intensity of the pharmacological effect on bone resorption. Non-nitrogen bisphosphonates appear to be less powerful than the nitrogenous compounds. By way of example, it is reported that the lowest subcutaneous dose leading to an inhibitory effect on a model of bone resorption in rats is 300 to 400 times lower with alendronic acid than with tiludronic acid (Geddes A., 1994, in “Bone and Mineral Research” Ed. Elsevier Science BV, p. 265-306).
This difference in pharmacological effect is found clinically in the indications for which these compounds benefit from marketing authorizations as medicinal products. Among these, osteoporosis in menopausal women is a preferred indication for bisphosphonic acid derivatives. A number of derivatives have a marketing authorization in this indication; this is the case for alendronic acid, at a daily dose of 10 mg per person orally (Lourwood D. L., 1998
, Pharmacotherapy
, 18, 779-789). Oth
Bardon Thierry
Thibaud Dominique
Ceva Sante Animale
Fay Zohreh
Jacobson & Holman PLLC
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